During an immune response, antigen-specific T cells are activated and expand to perform various effector functions that counteract and/or eliminate the invading pathogen. It has been shown that there is a massive increase in T cell number during clonal expansion under optimal conditions. When the pathogen has been eliminated, a contraction of T cell number occurs through cell death due to cytokine withdrawal but a small fraction of memory T cells are preserved. The generation of long-lived memory T cells is crucial for generating anamnestic immune responses to pathogens that are re-encountered. Anamnestic responses are the cellular basis of vaccination. On the other hand, programmed cell death is critical to achieve appropriate lymphocyte homeostasis and prevention of overexpansion of lymphocytes and lymphoid malignancy. Homeostasis of cell numbers and functions is generally carefully regulated during immune responses. We discovered that if an activated and cycling T cell is restimulated by its cognate antigen in the presence of interleukin 2 (IL-2) or other gamma chain cytokines, it is driven into an apoptotic death pathway, a process we have called restimulation-induced cell death (RICD) or propriocidal regulation. Following successful clonal expansion, memory T cells are formed from cells that escape RICD. Memory T cells of the CD4 type are segregated into two main subsets: central memory (TCM; CD44+CD62L+) and effector memory (TEM; CD44+CD62L-) T cells. Our laboratory has shown that TEM cells are far more sensitive to RICD than TCM cells or nave T cells (CD44-CD62L+)and thatIL-2 is necessary for TEM cell apoptosis. However, the molecular mechanism regulating apoptosis of memory cells remains poorly investigated. The IL-2 signaling pathway conveys signals from the cell surface to inside the cell primarily through a transcription factor called signal transducer and activator of transcription 5 (STAT5) which comes in two forms called a and b. We recently identified a patient with a novel heterozygous missense mutation in STAT5b which proved to be very revealing for the effect of IL-2. The clinical phenotype of this patient included immune thrombocytopenic purpura (ITP), lymphadenopathy, a high level of IgM antibodies but overall hypogammaglobulinemia, and a history of necrotizing granulomas in the lungs. Surprisingly, we found that the patient harbors a higher percentage of TEM cells in the blood compared to healthy subjects. We also found that the patient's TEM cells are strikingly resistant to RICD in vitro which could explain their accumulation in the blood. These findings are consistent with an excess of TEM cells that has been described in STAT5 deficient mice. Similar to TEM cells from the patient, TEM from STAT5b-deficient mice exhibited reduced RICD. In further experiments with human T cells, we observed that STAT5 inhibition using a chemical inhibitor caused a complete blockade of TEM RICD. In a transcriptomic analysis of the patients cells, RNA-sequencing revealed a global down-regulation of the IL2 pathway genes in patient T cells compared to healthy subjects. Moreover, we found that the mutant STAT5b protein was deficient in transcriptional activity using a luciferase reporter assay. When studied in various mixtures, with the wild-type protein, the mutant STAT5b was found to have a dominant-interfering effect. We also found that the patient's mother, who suffered from multiple sclerosis, also harbored the same mutation. Taken together, these data revealed that the homeostasis of memory T cells of the TEM subtype is controlled by IL-2 dependent apoptosis, correlated with a gene expression profile characteristic of IL-2, and that a failure of this pathway can lead to an immunoregulatory disease in humans.